Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults

Abstract

Context: In addition to trauma exposure, other factors contribute to risk for development of posttraumatic stress disorder (PTSD) in adulthood. Both genetic and environmental factors are contributory, with child abuse providing significant risk liability.

Objective: To increase understanding of genetic and environmental risk factors as well as their interaction in the development of PTSD by gene x environment interactions of child abuse, level of non-child abuse trauma exposure, and genetic polymorphisms at the stress-related gene FKBP5.

Design, setting, and participants: A cross-sectional study examining genetic and psychological risk factors in 900 nonpsychiatric clinic patients (762 included for all genotype studies) with significant levels of childhood abuse as well as non-child abuse trauma using a verbally presented survey combined with single-nucleotide polymorphism (SNP) genotyping. Participants were primarily urban, low-income, black (>95%) men and women seeking care in the general medical care and obstetrics-gynecology clinics of an urban public hospital in Atlanta, Georgia, between 2005 and 2007.

Main outcome measures: Severity of adult PTSD symptomatology, measured with the modified PTSD Symptom Scale, non-child abuse (primarily adult) trauma exposure and child abuse measured using the traumatic events inventory and 8 SNPs spanning the FKBP5 locus.

Results: Level of child abuse and non-child abuse trauma each separately predicted level of adult PTSD symptomatology (mean [SD], PTSD Symptom Scale for no child abuse, 8.03 [10.48] vs > or =2 types of abuse, 20.93 [14.32]; and for no non-child abuse trauma, 3.58 [6.27] vs > or =4 types, 16.74 [12.90]; P < .001). Although FKBP5 SNPs did not directly predict PTSD symptom outcome or interact with level of non-child abuse trauma to predict PTSD symptom severity, 4 SNPs in the FKBP5 locus significantly interacted (rs9296158, rs3800373, rs1360780, and rs9470080; minimum P = .0004) with the severity of child abuse to predict level of adult PTSD symptoms after correcting for multiple testing. This gene x environment interaction remained significant when controlling for depression severity scores, age, sex, levels of non-child abuse trauma exposure, and genetic ancestry. This genetic interaction was also paralleled by FKBP5 genotype-dependent and PTSD-dependent effects on glucocorticoid receptor sensitivity, measured by the dexamethasone suppression test.

Conclusions: Four SNPs of the FKBP5 gene interacted with severity of child abuse as a predictor of adult PTSD symptoms. There were no main effects of the SNPs on PTSD symptoms and no significant genetic interactions with level of non-child abuse trauma as predictor of adult PTSD symptoms, suggesting a potential gene-childhood environment interaction for adult PTSD.

Figure 1. FKBP SNPs and Main Genetic Effect on PTSD Symptoms and Interaction Effects With Non–Child Abuse Trauma Levels and Child Abuse

SNPs indicate single-nucleotide polymorphisms; PTSD, posttraumatic stress disorder. A, The plot shows the negative log₁₀ of the P value for the main genetic effect (filled circles), the interaction of FKBP5 SNP genotypes and non–child abuse trauma level (open squares), and the interaction of FKBP5 SNP genotypes and child abuse (open triangles) to predict adult PTSD symptoms. The x-axis shows the position of the SNPs on chromosome 6 and the y-axis shows the P value for the respective effects, plotted as the negative log₁₀ of the P value. Dotted line indicates P < .002. B, The position of the FKBP5 gene and its exons (filled rectangles) on chromosome 6 as well as a linkage disequilibrium (LD) plot of all tested SNPs using r² as the measure of LD is also shown. r²=1 indicates complete LD and is depicted by the darkest shade of blue. r²<1.0 are printed in the respective square for compared SNPs, with darker shades of blue representing higher levels of LD.

Figure 2. Glucocorticoid Receptor Sensitivity, PTSD, and FKBP5 SNPs

PTSD indicates posttraumatic stress disorder; SNPs, single-nucleotide polymorphisms. Mean serum cortisol concentration with 95% confidence interval (CI) is shown in participants who were tested at baseline and after 0.5 mg of dexamethasone (postdexamethasone suppression). The 4 panels represent the mean cortisol concentrations at baseline and postdexamethasone for individuals without probable PTSD (no PTSD) or with probable PTSD stratified by rs3800373, rs9296158, rs1360780, and rs9470080 genotypes. Individuals were categorized as risk allele carriers when they carried the C, A, T, or T alleles of these SNPs, respectively. Carriers of the AA, GG, CC, or CC homozygote genotypes of rs3800373, rs9296158, rs1360780, and rs9470080, respectively, were labeled as carrying the presumed protective genotypes. We found a significant interaction of genotype carrier- and PTSD-status on cortisol suppression (repeated measures analysis of variance: rs3800373, F_1,76=6.03, P=.02; rs9296158, F_1,78=8.76, P < .004; rs1360780, F_1,79=3.95, P =.05; rs9470080, F_1,77=5.32, P =.02; but also using permutation-based methods on percentage cortisol suppression). Although the risk alleles seem to be associated with less suppression (ie, glucocorticoid receptor resistance) in the no PTSD group, they are associated with greater suppression of cortisol from baseline to postdexamethasone in the group with PTSD. For rs9296158 GG carrier with no PTSD and rs9470080 CC carrier with no PTSD, the lower bound of the 95% CI had a negative value and was truncated at zero.